When travelling across a number of time zones or when working changing shifts such as e.g. night shifts, the body clock becomes out of synchronization with the actual time, as it experiences daylight and darkness contrary to the rhythms to which it has grown accustomed: the body's natural pattern is upset, as the rhythms that dictate times for eating, sleeping, hormone regulation and body temperature variations are no longer synchronized to the environment nor to each other in some cases. To the degree that the body cannot immediately re-align these rhythms, it is jet lagged.
Jet lag is characterized by decreased alertness, night time insomnia, poor overall performance (Tapp and Natelson 1989), impaired cognitive skills (Cho et al. 2001), loss of appetite, depressed mood, reduced psychomotor coordination, and gastrointestinal disturbances (Waterhouse et al. 2007). The severity and extent of these symptoms depend on the direction and speed of travel and the number of time zones crossed (Waterhouse et al. 2007; Arendt et al. 2009; Haimov et al. 1999; Srinivasan et al. 2008).
Research has suggested that individuals exposed to chronic jet lag may experience accelerated malignant growth (Filipski et al. 2004) and temporal lobe atrophy combined with spatial cognitive deficits (Cho et al. 2001). It has been shown that rodents subjected to chronic jet lag suffer from cardiomyopathies (Penev et al. 1998) and hastened death upon aging (Davidson et al. 2006).
Circadian clocks are oscillators driven by interlocked positive and negative transcriptional/translational feedback loops. The circadian transcriptional activators circadian locomotor output cycles kaput (CLOCK) and aryl hydrocarbon receptor nuclear translocator-like (ARNTL; also referred to as BMAL1) turn on period (Per1, Per2, and Per3) and cryptochrome (Cry1 and Cry2) genes. PER and CRY proteins are negative regulators repressing CLOCK/ARNTL-mediated transactivation (Dunlap 1999; Reppert and Weaver 2001; van der Horst et al. 1999).
A second loop involves positive and negative regulation of Arnt1 expression through RAR-related orphan receptor α (RORα) and nuclear receptor subfamily 1, group D, member 1 (NR1D1; also known as REV-ERBα), respectively (Preitner et al. 2002). The transcription factor D site albumin promoter binding protein (DBP) regulates rhythmic activation of downstream target genes (Ripperger et al. 2000), thereby serving as relay mediating the output of the circadian oscillator. The master pacemaker of the hypothalamic suprachiasmatic nuclei (SCN) and also peripheral oscillators all rhythmically express clock genes (Welsh et al. 2004). The SCN appears to synchronize peripheral oscillators present in, for example, the cerebral cortex (Yan et al. 2000; Abe et al. 2001), the retina (Tosini et al. 1996), the liver (Yamazaki et al. 2000), the kidney (Yoo et al. 2004), and the pancreas (Damiola et al. 2000; Liu et al. 2007; Oishi et al. 2000; Schibler et al. 2003) through hormonal and neuronal pathways (Schibler et al. 2003; Perreau-Lenz et al. 2004). Peripheral clocks translate clock time into physiologically meaningful signals via rhythmic activation of clock-controlled genes (Storch et al. 2002; Panda et al. 2002). The temporal disorganization of the circadian system during jet lag is likely to disrupt overall physiological coordination and, hence, be the cause of most jet lag-associated symptoms (Arendt et al. 2009).
To date, surprisingly little is known about the molecular processes underlying resynchronization of internal and external rhythms during jet lag. Pioneering studies with rodents expressing a period gene-driven luciferase reporter have provided inroads to understanding the underlying mechanism (Yamazaki et al. 2000). It was proposed that overall clock resetting is initiated at the level of the SCN, with rapid reentrainment of period gene rhythms followed by that of cryptochrome genes (Reddy et al. 2002). Reddy and colleagues provide evidence that cryptochrome rhythm entrainment in the SCN closely correlates with that of behaviour (Reddy et al. 2002).
Another aspect of perturbation was shown at the level of SCN morphology, where cells can be separated in ventral and dorsal regions that show different resetting kinetics during the period of desynchrony (Davidson et al. 2009).
Collectively, the results of these studies, which included a limited number of tissues and circadian genes, suggest that coordination of clock gene expression is globally disrupted during jet lag.
At present, common strategies to alleviate jet lag and the syndromes and diseases associated therewith aim at adjusting the body clock to the new time zone prior to travel (Waterhouse et al. 2007). Therefore, most treatments are based on pre-flight plans, including long-term light conditioning, sometimes in combination with timed melatonin administration (Arendt et al. 2009).
Furthermore, it has recently been shown that in hamsters, the phosphodiesterase inhibitor sildenafil enhances circadian responses to light and accelerates reentrainment after phase advances of the LD cycle (Agostino et al. 2007).
However, despite the above described advances in understanding the mechanisms underlying jet lag and in the development of treatments to alleviate the effects of jet lag, no satisfying therapeutic is at present available for the treatment of symptoms and diseases associated with jet lag.
The findings of the present invention not only substantiate the importance of glucocorticoid rhythms in jet lag adaptation, but also provide a novel therapeutic model for the treatment of jet lag and its associated symptoms.